KRAS-Driven Cancers Are Dependent on METTL13-Mediated eEF1A Methylation

Upregulation of protein translation is a hallmark of many oncogene-driven tumors and is essential to sustain neoplastic growth. However, the mechanisms underlying this increase in protein synthesis and whether it represents a potential therapeutic vulnerability remain incompletely understood. Liu, Hausmann, and colleagues found that the eukaryotic elongation factor 1α (eEF1A), a GTPase that is a nonribosomal component of the translational machinery, is dimethylated at lysine 55 (eEF1AK55me2) by the lysine methyltransferase METTL13. In vitro methylation assays and quantitative proteomics analysis defined methylation of eEF1AK55 as the primary physiologic activity of METTL13. METTL13-mediated methylation of eEF1AK55 enhanced the basal GTPase activity of eEF1A, leading to an increase in global protein synthesis in pancreatic and lung cancer cells. Expression of METTL13 and methylation of eEF1AK55 were increased in human pancreatic and lung cancer samples and correlated with poor patient survival, suggesting a role for METTL13-driven modification of eEF1A in tumorigenesis. Consistent with this idea, depletion of METTL13 or eEF1A inhibited pancreatic cancer cell proliferation, and this effect could be rescued by expression of wild-type METTL13 or eEF1A, but not catalytically inactive METTL13 or eEF1A with a mutation at K55. In addition, deletion of METTL13 and subsequent loss of eEF1AK55me2 suppressed the growth of KRAS-driven tumors in mice and primary human pancreatic and lung cancer patient-derived xenografts (PDX). Furthermore, depletion of METTL13 increased the sensitivity of cancer cells to drugs targeting growth signaling via the PI3K–mTOR and MAPK pathways; combined deletion of METTL13 and treatment with a dual pan-PI3K/mTOR inhibitor significantly inhibited pancreatic and lung PDX tumor growth. These findings identify METTL13-catalyzed methylation of eEF1AK55 as a critical mechanism by which KRAS-driven tumors sustain increased protein synthesis to promote tumorigenesis and suggest the METTL13–eEF1AK55me2 axis as a potential therapeutic target.

Liu S, Hausmann S, Carlson SM, Fuentes ME, Francis JW, Pillai R, et al. METTL13 methylation of eEF1A increases translational output to promote tumorigenesis. Cell 2018 Dec 28 [Epub ahead of print].

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